Disability is common in the elderly and is a major public health concern because it is associated with reduced quality of life and increased service utilization. Alzheimer's Disease (AD) is a major cause of disability. Despite its importance, relatively little research has been done to understand the course of functional decline in AD, or the mechanisms that drive individual trajectories of declines in everyday function. The loss of everyday abilities in the setting of a developing degenerative dementia such as AD is a progressive process. That is, functional abilities decline along a continuum, similar to cognition, reflecting progression of the underlying disease. A major emphasis of the proposed study is to better understand the full continuum of functional decline, particularly early and subtle problems that precede and predict disability (disability being defined as dependency in major life domains such as instrumental and basic activities of daily living). The development of disability results from a complex interplay between numerous factors. In AD, clearly cognitive decline is a major determinant; a focus of this project is to better understand how specific cognitive impairments contribute to deficits in specific domains of everyday function. In addition to cognition, however, there are likely a large number of other factors that further contribute to and help explain individual variability in rates and patterns of decline. With previous NIA support (AG021511) we developed a novel and sensitive approach to measuring `functional limitations' - functional problems that likely precede the development of frank disability. Using this approach we have demonstrated that Mild Cognitive Impairment (MCI) is associated with functional limitations intermediate to normal aging and dementia. Using a prospective, longitudinal research design, Aim 1 of this project focuses on characterizing the intermediate stages and transition points between normal function and disability. Aims 2-4 seek to understand the heterogeneity we see in individual functional trajectories by examining potential sources of this variability. Specifically, we will examine how neuropsychological, neuropsychiatric, and motor impairments influence the disability pathway. In addition, we will examine how associated risk factors, such as general health status and education, modify the trajectories of functional decline. An improved understanding of trajectories of functional decline, and the factors that contribute to individual rates and patterns of decline, will have important clinical relevance for: early diagnosis and prognosis; treatment development and the early implementation of supportive services and care planning; and the measurement of disease progression and the effects of potential disease modifying treatments. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is a major cause of disability (declines in real-world abilities such as manage one's finances or medications, driving, etc.), which directly reduced quality of life for patients and their caregivers, and lead to increased economic burden. Despite their importance, we do not clearly understand how functional problems develop and progress in association with AD, nor do we understand the specific factors that contribute to progressive disability. Understanding how disability develops in AD will have far reaching applications to public health, preventative medicine, and treatment development, and will also have important implications for the individualized care of patients.